Breast cancer is a physically and emotionally devastating diagnosis affecting over 2.3 million Americans living with the disease and killing over 100 women each day. Although the prognosis for this disease is gradually improving with the development of chemotherapeutic drugs, many aggressive forms of breast cancer are resistant to chemotherapy and result in a 10% mortality rate within 5 years of diagnosis. A compound known as sphingosine 1-phosphate (S1P) may be a major determinant of the aggressiveness and drug resistance of breast cancer. S1P is a small molecule normally present in high concentrations in the blood that accelerates the progression of breast cancer. It does this by promoting the growth and spreading of cancer cells and by stimulating the formation of new blood vessels, thereby increasing the supply of oxygen and nutrients to the tumor. Evidence suggests that these actions are largely the result of the stimulation of a specific receptor for S1P called S1P3. Since S1P has been shown to be a general growth stimulant for breast cancer cells, and since it causes normal blood vessels to grow uncontrollably in tumors, it is likely that inhibiting S1P3 will slow the progression of most forms of breast cancer and sensitize the tumors to treatment with conventional chemotherapy. Animal studies suggest that loss of this receptor is not associated with undesirable effects, providing evidence for the safety of this approach. However, there are currently no reports of any drug compounds that specifically block S1P3. Successful completion of the proposed project will 1) characterize the potential clinical relevance of targeting S1P3, and 2) use an innovative and versatile technology to produce drug candidates. It is likely that these drug candidates will ultimately result in a new breast cancer treatment that will increase the effectiveness of chemotherapy while reducing the often debilitating side effects associated with these drugs. PUBLIC HEALTH RELEVANCE:Breast cancer is the most common form of cancer in the U.S. causing the death of over 35,000 American women each year. Much of this mortality can be averted by increasing the effectiveness and reducing the side effects of conventional chemotherapy. The proposed research will develop a drug specifically designed to interrupt cellular processes known to promote growth of breast tumors, thus limiting cancer growth and improving the effectiveness of chemotherapy at lower doses. [unreadable] [unreadable] [unreadable]